The present invention relates generally to devices, systems and methods of delivery of a slurry to a patient and, particularly, to devices, systems and methods of delivering a slurry including living cells to a patient.
The following information is provided to assist the reader to understand the invention disclosed below and the environment in which it will typically be used. The terms used herein are not intended to be limited to any particular narrow interpretation unless clearly stated otherwise in this document. References set forth herein may facilitate understanding of the present invention or the background of the present invention. The disclosures of the references cited herein are incorporated by reference.
In a number of medical procedures, it is desirable to inject a multi-component injection medium into a patient. A multi-component injection medium is one that contains two or more effectively immiscible or insoluble materials or phases. (The term effective is used because they may ultimately dissolve or mix, but not in the time frame of interest for the imaging procedure.)
One example of such a medical procedure is ultrasound imaging, where small bubbles are contained or delivered in a liquid. The injection medium is injected into the veins, arteries, or tissue of the patient and provides increased ultrasound image signal or contrast. See, for example, U.S. Pat. No. 6,575,930.
A second example of delivery of a multi-component medium occurs in cell therapies in which cells in a carrier liquid are injected into the patient. The cells do not dissolve in the carrier liquid. Depending upon the disease or condition to be treated, the injection medium can be injected into arteries, tissue, or veins. A therapeutically effective fraction of the cells preferably remains intact and alive, and so constitute one material that is immiscible in the liquid or blood used for the liquid component of the injectate.
A third example of delivery of a multi-component medium is the delivery of cells on carrier beads or in or on a cell matrix of some kind. An example of such a medium is SPHERAMINE®, a treatment for Parkinson's disease being tested by Titan Pharmaceuticals, Inc. of San Francisco, Calif. SPHERAMINE is, for example, described in U.S. Patent Application Publication No. 2006/0037634. SPHERAMINE treatment involves implanting human retinal pigment epithelial cells on cell-carrying microcapsules or microspheres into the brain. Cell-carrying microcapsules and other microcapsules are described, for example, in EP 0554352 and EP 0222718. Such microcapsules can, for example, be made of glass, other silicon oxides, polystyrene, polypropylene, polyethylene, polyacrylamide, polycarbonate, polypentene, acrylonitrile polymers, nylon, amylases, collagen, polysaccharides, magnetite beads or formed of a gel or gelatin. The typical size of the microcapsules is approximately 10-500 microns. The cells are grown or implanted onto or into the microcapsules. The microcapsules can, for example, be implanted into sensitive tissue such as the brain to provide a medical treatment.
A fourth example of a multi-component medium includes small beads or spheres that can be used to embolize a tumor. The spheres are sufficiently large that they cannot pass through the smaller down stream vessels, but are sufficiently small that they can be carried along by a fluid through a catheter into the desired vessel. These spheres can optionally incorporate chemicals that provide pharmaceutical action, such as chemotherapy drugs for reducing (in size and/or number) or eliminating tumors. The spheres can also incorporate radioactive elements that provide local radiation therapy.
A fifth example of a multi-component medium includes small beads or spheres (microspheres) used to deliver gene therapy to tissues. Microspheres may be used to deliver gene therapies to solid tumors either through direct injection into tissue or through intravascular delivery into the vessels that feed a tumor. See: Dass, C. R., et. al., “Microsphere-Mediated Targeted Gene Therapy of Solid Tumors”, Drug Delivery, Volume 6, Number 4, 1 Oct. 1999, pp. 243-252(10). Gelatin or other microspheres may also be used as vectors to deliver gene or protein therapy into tissues for angiogenesis, or other regenerative medicine therapies. Administration routes include antegrade arterial injection, retrograde venous injection, and direct injection into tissue. The use of gelatin microspheres may offer some advantages over the use of viral vectors for delivering gene therapy agents, which may include additional regulatory concerns over the use of viral delivery vectors for gene therapy administration. See: Hoshino, K, et al., “Three catheter-based strategies for cardiac delivery of therapeutic gelatin microspheres”, Gene Therapy (2006) 13, 1320-1327. Microspheres for gene therapy delivery may also be made of biodegradable polymers that encapsulate the functional gene therapy vector. See U.S. Pat. No. 6,048,551.
In such multi-component mediums and similar mediums, it is common that one material is more dense than the other, and that some separation of the two materials occurs as a result of gravity. The rate of separation depends upon many factors, including, for example, differences in the densities, the size of the particles or agglomerations of particles, and the viscosity of the fluid(s) involved. Other factors that influence the rate of separation include the type of fluid, i.e. Newtonian or non-Newtonian, as well as particle to particle and particle to container interactions.
To improve or maintain consistency of delivery, it is desirable to either prevent this separation or to resuspend the components if significant separation does occur.
U.S. Patent Application Publication No. 2001/0018571 discloses a device that provides a suspended agent without additional mechanical mixing to affect resuspension. That device divides a total volume of a sedimenting agent into a network of sub-volumes and includes ports for an inflow and an outflow of a propellant fluid to releases the sub-volumes of agent from the device.
There are a number of patents which disclose separately storing and then uniformly mixing two materials, often a powder and a liquid, with the desired result of uniform mixing, dispersion, or dissolution of one material into the other, with subsequent dispensing or delivery. Among these are the following references: U.S. Patent Application Publication Nos. 2004/0127846 and 2004/0092883; and U.S. Pat. Nos. 6,699,214; 3,951,387; 4,808,184; 4,172,457; 5,425,580; 5,810,773; 5,908,054; 6,062,722; 5,176,446; 6,432,604; 6,814,482; 5,385,564; 5,120,135; 3,370,754; 3,477,432; 3,606,094; 5,354,285; 5,779,668; 3,373,906; 5,071,040; 3,831,903; 5,240,322; 4,704,105; Re. 32,974; 5,275,582; 4,543,094; 7,244,248; 6,706,020; 6,726,650; 6,758,828.
U.S. Pat. No. 6,575,930 discloses a number of devices, systems and methods to facilitate or to improve the initial creation and/or mixing of, for example, contrast medium, and to agitate the contrast medium to maintain a relatively uniform distribution of the contrast enhancing agent or particles throughout the liquid contrast medium prior to and/or during an injection procedure.
The agitation mechanisms or devices of U.S. Pat. No. 6,575,930 can be categorized broadly in three classes which can be used separately or in combination. In the first class of agitation mechanism, the contrast medium is agitated by bulk movement of the entire storage volume or container in which the contrast medium is prepared and/or kept prior to and/or during injection into the patient. The second class of agitation mechanism agitates the contrast medium within the storage volume or container without bulk movement of the storage volume or container. The third class of agitation mechanism agitates the contrast medium by circulating/transporting the contrast medium using an agitation pump. For example, the contrast medium can be transported between two storage volumes or containers in an alternating manner.
Cell therapies as described above involve delivery of living cells (for example, single cells, agglomerations of cells, or cells on microcarriers or scaffolds). The delivery of live cells provides a number of unique challenges in regards to maintenance of a suspension or resuspension. See, for example, Wong, K. et al., Overview of Microcarrier Culture, Cellular Bioprocess Technology, University of Minnesota, 1-8 (2004). For example, cells can be damaged if the shear rate in the fluid is too high. Dewitz et al. reported significant effects on white cells in the stress range of 100-300 dynes/cm.sup.2 and nearly complete destruction at 600 dynes/cm.sup.2. Dewitz, T S, Hung T C, Russel R M, McIntire L V. Mechanical Trauma in Leukocytes. Journal of Laboratory and Clinical Medicine. 90: 728-736 (1977). The effect of stress is also time dependent. See, for example, Kameneva, M. V. et al., Effects of Turbulent Stress upon Mechanical Hemolysis: Experimental and Computational Analysis, ASAIO Journal, 418-423 (2004). The delivery of cells and some of the unique challenges associated therewith are also discussed in PCT Publication Nos. WO 2007/056247 and WO 2007/053779.
Further, there are some indications that significantly lower stress can damage non-blood cells. See, for example, Mardikar, S. H. and Niranjan, K., Observations on the Shear Shear Damage To Different Animal Cells In a Concentric Cylinder Viscometer, Communications to the Editor, Biotechnology and Bioengineering, 68:6, 697-704 (2000). Moreover, damage that is not immediately lethal or destructive of cells can cause significantly shortened lifetimes. See, for example, Blood Cell Damage by Artificial Organ Devices is Focus of University of Pittsburgh Scientists Talk at International Congress of Biorheology, News Bureau, University of Pittsburgh Medical Center (UPMC), 1-3.
Cells also tend to have higher cohesion and adhesion than, for example, ultrasound contrast bubbles and inanimate particles such as embolization spheres. In addition, if cells are killed, their DNA and other cellular components may be released, and the DNA and other cellular components, being relatively long molecules, are “sticky”.
Multi-component injection mediums with cells and some type of cell substrate, scaffold, beads, or support spheres are more difficult to maintain in suspension as a result of several of the factors mentioned above.
In addition, especially for multi-component injection mediums, cells, or cells on carriers being delivered to tissue, it is desirable to have a concentrated slurry, often as concentrated as is reasonably achievable, in contrast with applications for contrast or drug delivery where the medium is being delivered into blood vessels and some extra water or liquid is minimally detrimental.
It is thus desirable to develop resuspension devices, systems, and methods suitable for use in cell therapies which creates a sufficiently flowable slurry or suspension of a consistent concentration and flow properties. Such devices, systems and methods can also have application to situations beyond cell therapies wherein a multi-component injection medium is to be delivered to a patient.